The goals of this project are to develop in the laboratory, using model systems and primary CLL cells in vitro[unreadable] an understanding of the mechanisms of action of anticancer agents acting alone and in mechanism-based[unreadable] combinations. This knowledge base will provide rationales for the design and evaluation of clinical trials that[unreadable] will test hypotheses regarding the actions and interactions of these agents in CLL cells in patients during[unreadable] therapy. Thus, the central hypothesis we will test is that knowledge derived from an understanding of the[unreadable] metabolism, mechanisms of action, and the interactions of new anticancer therapeutics can be used to[unreadable] design and evaluate novel therapeutic regimens for the treatment of patients with CLL. To achieve these[unreadable] goals, we will address the following questions: 1. Do nucleoside analogs with novel actions provide[unreadable] pharmacological and clinical advantages over fludarabine for the treatment of B-CLL? Our focus here will be[unreadable] on the new nucleoside analog, clofarabine which has pharmacologic properties different from fludarabine. 2.[unreadable] Can strategies to reduce survival proteins selectively kill CLL cells? We are developing 8-chloro-adenosine[unreadable] ribonucleotide analog that reduces cellular bioenergy and blocks transcription. Also, we will evaluate the[unreadable] transcription-directed actions of flavopiridol. The actions of each of these agents decreases anti-apoptotic[unreadable] proteins in CLL cells. 3. Will mechanism-based combinations of cytotoxic agents improve outcome in CLL[unreadable] patients? The cellular responses to inhibition of excision DNA repair processes will be investigated in CLL[unreadable] cells, and extended to new DNA damaging agents and drugs that inhibit DNA repair. 4. Can orsaponin, a[unreadable] synthetic natural compound with potent anticancer activity and unique mechanism of action, be used as a[unreadable] novel agent for treatment of CLL? The action mechanism(s) of this novel agent that selectively kills CLL[unreadable] cells independent of p53 status will be investigated in preparation for clinical development. Interactions with[unreadable] other projects in this program will strengthen our investigations.